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We have investigated how doubly selective synthetic mimics of antimicrobial peptides (SMAMPs), which can differentiate not only between bacteria and mammalian cells, but also between Gram-negative and Gram-positive bacteria, make the latter distinction. By dye-leakage experiments on model vesicles and complementary experiments on bacteria, we were able to relate the Gram selectivity to structural differences of these bacteria types. We showed that the double membrane of E. coli rather than the difference in lipid composition between E. coli and S. aureus was responsible for Gram selectivity. The molecular-weight-dependent antimicrobial activity of the SMAMPs was shown to be a sieving effect: while the 3000 g mol(-1) SMAMP was able to penetrate the peptidoglycan layer of the Gram-positive S. aureus bacteria, the 50000 g mol(-1) SMAMP got stuck and consequently did not have antimicrobial activity.

Synthetic mimics of antimicrobial peptides (SMAMPs) are known to disrupt cellular membranes in aqueous media. The impact of ionic strength, or the salt concentration, on membrane activity of these SMAMPs is an important issue since some AMPs are known to lose their activity at higher salt concentrations. In this report, the effect of salt concentration on membrane activity was evaluated using fluorescence dye leakage assays. Salt concentration did not affect the membrane activity of these SMAMPs significantly except for the 100% anionic vesicles (phosphatidylglycerol (PG) or phosphatidylserine (PS) only), where membrane activity decreased with increasing salt concentration. The results also indicated that the membrane activity of SMAMPs with monoamine side chains is independent on ionic strength against cardiolipin (CL) vesicles; however, SMAMPs containing bis- or trisamines exhibited salt concentration dependent membrane activity for CL liposomes.

In this study, amphiphilic polyoxanorbornene with different quaternary alkyl pyridinium side chains were synthesized. The biological efficiencies of these polymers, with various alkyl substituents, were determined by bacterial growth inhibition assays and hemolytic activity (HC 50 ) against human red blood cells (RBCs) to provide selectivity of these polymers for bacterial over mammalian cells. A series of polymers with different alkyl substituents (ethyl, butyl, hexyl, octyl, decyl and phenylethyl) and two different molecular weights (3 and 10 kDa) were prepared. The impact of alkyl chain length divided the biological activity into two different cases: those with an alkyl substituent containing four or fewer carbons had a minimum inhibitory concentration (MIC) of 200 μg. mL -1 and a HC 50 greater than 1650 μg. mL -1 , while those with six or more carbons had lower MICs < 12.5 μg. mL -1 and HC 50 ≤ 250 μg. mL -1 . Using MSI-78, the potent Magainin derivative which has an MIC=12.0 μg·mL -1 and HC 50 = 120 μg·mL -1 , as a comparison, the polymers with alkyl substituents ≤C 4 (four carbons) were not very potent, but did show selectivity values greater than or equal to MSI-78. In contrast, those with alkyl substituents ≥C 6 were as potent, or more potent, than MSI-78 and in three specific cases demonstrated selectivity values similar to, or better than, MSI-78. To understand if these polymers were membrane active, polymer induced lipid membrane disruption activities were evaluated by dye leakage experiments. Lipid composition and polymer hydrophobicity were found to be important factors for dye release.

Infectious diseases and antibiotic resistance are now considered the most imperative global healthcare problem. In the search for new treatments, host defense, or antimicrobial, peptides have attracted considerable attention due to their various unique properties; however, attempts to develop in vivo therapies have been severely limited. Efforts to develop synthetic mimics of antimicrobial peptides (SMAMPs) have increased significantly in the last decade, and this review will focus primarily on the structural evolution of SMAMPs and their membrane activity. This review will attempt to make a bridge between the design of SMAMPs and the fundamentals of SMAMP-membrane interactions. In discussions regarding the membrane interaction of SMAMPs, close attention will be paid to the lipid composition of the bilayer. Despite many years of study, the exact conformational aspects responsible for the high selectivity of these AMPs and SMAMPs toward bacterial cells over mammalian cells are still not fully understood. The ability to design SMAMPs that are potently antimicrobial, yet nontoxic to mammalian cells has been demonstrated with a variety of molecular scaffolds. Initial animal studies show very good tissue distribution along with more than a 4-log reduction in bacterial counts. The results on SMAMPs are not only extremely promising for novel antibiotics, but also provide an optimistic picture for the greater challenge of general proteomimetics.

The pyrene-1,3,6-trisulfonate scaffold is introduced as an internal cofactor for histidine-rich p-octiphenyl s-barrels with catalytic and ion channel activity to mediate binding and conversion of otherwise inaccessible benzaldehyde substrates. Up to 170,000-fold accelerations of amide, ester, and carbonate hydrolysis, high substrate diversity, high chemoselectivity, and absence of enantioselectivity are reported.

Intermediate internal charge repulsion (ICR) is required to create synthetic pores with large, stable, transmembrane, and variably functionalized space. This conclusion is drawn from maximal transport and, in one case, catalytic activity of p-octiphenyl s-barrel pores with internal lysine, aspartate, and histidine residues around pH 7, 6, and 4.5, respectively. pKa Simulations corroborate the experimental correlation of intermediate ICR with activity and suggest that insufficient ICR causes pore implosion' and excess ICR pore explosion'. Esterolysis experiments support the view that the formation of stable space within multifunctional p-octiphenyl s-barrels requires more ICR in bilayer membranes than in H2O. Multivalency effects are thought to account for p-octiphenyl s-barrel expansion with increasing number of s-sheets, and proximity effects for unchanged pH profiles with increasing s-sheet length. Q-TOF-nano-ESI-MS barrel-denaturation experiments indicate that contributions from internal counterion effects are not negligible. The overall characteristics of p-octiphenyl s-barrel pores with internal lysine, aspartate, and histidine residues, unlike de novo a-barrels' and similarly to certain biological channels, underscore the usefulness of rigid-rod molecules to preorganize complex multifunctional supramolecular architecture.

Cell penetrating peptides (CPPs) and their synthetic analogs are of widespread interest. Here we report that guanidine rich small molecules can be potential membrane transporters in the presence of hydrophobic counteranion activators. To our knowledge, this is the first example of small molecules that mimic the anion-activated transport function of CPP.

The current study is aimed at investigating the effect of fine-tuning the cationic character of synthetic mimics of antimicrobial peptides (SMAMPs) on the hemolytic and antibacterial activities. A series of novel norbornene monomers that carry one, two, or three Boc-protected amine functionalities was prepared. Ring-opening metathesis polymerization (ROMP) of the monomers, followed by deprotection of the amine groups resulted in cationic antimicrobial polynorbornenes that carry one, two, and three charges per monomer repeat unit. Increasing the number of amine groups on the most hydrophobic polymer reduced its hemolytic activity significantly. To understand the membrane activity of these polymers, we conducted dye leakage experiments on lipid vesicles that mimic bacteria and red blood cell membranes, and these results showed a strong correlation with the hemolysis data.

We report that decreasing beta-sheet length in homologous multifunctional rigid-rod beta-barrels with internal histidines increases ion channel stability by three orders of magnitude, reduces binding activity by four orders of magnitude, and reduces esterase activity up to 22-times. These results are further used to evaluate methods employed to characterize suprastructure and activity of synthetic multifunctional pores formed by p-octiphenyl beta-barrels with emphasis on applicability of the Hille model to determine internal diameters and the Woodhull equation to locate internal active sites.

A family of synthetic mimic of antimicrobial peptides (SMAMP), amphiphilic meta-phenylene ethynylene (mPE) molecules show a wide range of antimicrobial activity and specificity. The interaction of a specifically active mPE molecule (AMO-2) with mixed DOPE/DOPG lipid was studied by solid-state NMR. The AMO-2 molecules do not preferentially interact more strongly with either lipid component, but rather are well dispersed in the lipid matrix. AMO-2 intimately interacts with all parts of lipid molecules, including head groups. Magic-angle spinning sideband analysis indicated that in samples with co-existing lamellar and inversed hexagonal phases (HII), neither lipid component aggregate in either phase. The presence of AMO-2 molecules causes dynamic disorder in lipid head groups, as evidenced by the broadening of both static and MAS 31P spectra. AMO-2 molecules do not massively transform the lamellar lipid into HII phase.